A Life in Science RewardedYears of research elucidates how we recognize odors, and how the brain works

Nobel Prize winner Richard Axel

Discoveries made at CUMC about the sense of smell go beyond providing a description of what most people think is merely an aesthetic sense. Instead, understanding how the brain distinguishes among a bewildering array of different odors gives scientists a much greater understanding of how the brain works.

"Odors generate specific behaviors and specific thoughts and how that happens is still an unsolved and fascinating mystery in brain science," says Richard Axel, M.D., University Professor of Biochemistry and Molecular Biophysics and Pathology and recipient of the Nobel Prize in Physiology or Medicine on Oct. 4. "Knowing how our perceptions of the external world, including smell, impact our emotions and our behavior will be extremely important in thinking about diseases like schizophrenia to understand how the brain works."

When Dr. Axel and his former postdoctoral researcher Linda Buck, Ph.D., of the Fred Hutchinson Cancer Research Center and a professor at the University of Washington in Seattle, began their work in the late 1980s, very little was known about the sense of smell.

In 1985, Dr. Buck came across a paper describing the unsolved question of how odors are detected in the nose and was immediately hooked by "the monumental problem and a wonderful puzzle."

ONE NOBEL LAUREATE'S HUMBLE BEGINNINGS

During CUMC's celebration of Dr. Richard Axel's Nobel Prize, Dr. Bernard Weinstein, M.D., D.Sci., (Hon.), Frode Jensen Professor of Medicine, director emeritus of the Herbert Irving Comprehensive Cancer Center, and Dr. Axel's first mentor, told the story of Dr. Axel's early foray into the world of scientific research:

"In 1964, when I was a young professor here and Richard was a kid, I got a call from a physician friend who said that he was taking care of a patient, Richard's mother. And Richard's mother said to my friend, very proudly, that her son had graduated Stuyvesant High School with honors and was about to start at Columbia College. [She asked my friend], "Can you find him a job at a research lab?" So he called me and said, "Bernie, take this kid, he's really smart." That was the understatement of the times.

I was pleased to have Richard in the laboratory. The only job I had was for a glassware washer. You'll hear many accolades about Richard, but I want to tell you, frankly, he's a terrible glassware washer: the bottoms were murky, test tubes were broken, and pipettes were losing their tips. But in the midst of this, Richard was poking around asking why we're doing this experiment or that, or why we're not trying something else. So we fired him as the lab's glassware washer and rehired him to do research.

Within two or three years, we had three publications with him as senior author. I've never seen an undergraduate student who was so productive and, of course, with such great promise. Fortunately most of his subsequent career has been at Columbia so I've continued to be enriched by his work, to deepen our friendship and be constantly stimulated by his intellect.

As you know, I'm a cancer researcher so I can't take credit for him entering the field of neurobiology or for opening our insights into olfaction. But as I think about it I may have inadvertently done that. Because when Richard was in the lab I told him that being a scientist has a certain intuitive quality. A good scientist has to have a nose for which field to work in. He thought I said he should work on the nose.

Finally, I want to say as a senior researcher, as I look back on my own career, the greatest satisfaction is to remember the young people who have come through my laboratory and to watch their own careers evolve. Never did I dream that a former student of mine would receive the highest accolade in science, a Nobel prize. I'm thrilled and gratified. Frankly, I take great pride. As we say in Swedish: Mazel Tov!"

"This paper opened up a fascinating new world for me," she wrote earlier this year in the journal Cell. "It was estimated that humans could perceive 10,000 or more chemicals as having distinct odors. How could the olfactory system detect such an enormous diversity of chemicals? And how could the nervous system translate this complexity of chemical structures into a multitude of different odor perceptions?"

The questions would remain unanswered unless the receptors responsible for picking up odorants in the air were identified. In 1988, Dr. Buck, working in Dr. Axel's lab at P&S, started tracking them down.

Several initial attempts failed. "Linda was an extremely creative and tenacious Fellow," Dr. Axel says. "The solution to this problem took quite a long time, but the thoughtfulness of her approach made me think she would eventually succeed."

In 1991 Drs. Axel and Buck broke the field open when they published a paper describing an enormous family of genes in mice that coded for 1,000 different receptors. The study was reported in newspapers and other news media worldwide. Later work revealed about 350 functional receptor genes in humans.

"We were quite surprised that up to 5 percent of the genome was taken up by odor receptors," says Dr. Axel, also a member of Columbia's Center for Neurobiology and Behavior. "That's a sharp distinction to the three genes that the visual system uses to discriminate several hundred different hues. It shows that a system like the visual system would be inadequate to distinguish among the rich variety of odors in the environment."

Gerald Fischbach, M.D., executive vice president and dean, says the finding ranks among the most important discoveries of the past 50 years: "The discovery of the genes opened up a field of sensory biology that didn't exist before."

Once the receptor genes were identified, both researchers independently moved to the more complex question of how the brain knows what the nose smells, with the support of the NIH and the Howard Hughes Medical Institute, where the two are investigators. Their labs and others have revealed that part of the answer is that each odor produces a unique spatial pattern, or map, of neuronal activity in the brain's olfactory center. If the olfactory center was laid out like a map of the United States, it would be as if the aroma from a rose would light up Boston, New York, and San Francisco, while rotting food would light up Los Angeles and Denver.

The question now, Dr. Axel says, is figuring out how an organism uses these odor maps. We can look down at the maps of activity in an organism's brain and see what it's smelling, but how does the process actually work within an organism?

"To know that the world is interested in our work will, I think, intensify our efforts toward reaching an answer," Dr. Axel says.